Transcript The Schwann cell

‫بسم هللا الرحمن الرحیم‬
Doctoral Seminar
Title: The neuroimmunology of Schwann cell
Presented by: M. Sh. Mojadadi
Advisor: Dr. M. Ebtekar
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Outline

Introduction to the Schwann cell

Schwann cell development and myelination

Cytokine and chemokine interactions with Schwann cells

Schwann cells as immunomodulatory cells

Guillain-Barre syndrome and the Schwann cell
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Schwann cells: The present and the future
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Introduction to the Schwann cell
History
 Theodor Schwann: (1810-1882)
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Introduction to the Schwann cell
The Schwann cell

Two major components of nervous system:
1: Central nervous system (CNS) – brain and spinal cord
2: Peripheral nervous system (PNS)
a) Axonal processes extending toward or away from CNS (nerves)
b) Ganglia (aggregations of nerve cell bodies outside CNS)
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Introduction to the Schwann cell
Axon may be unmylenated or may be myelinated by either:
Oligodendroglia in CNS
or
Schwann cells in PNS
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Introduction to the Schwann cell
The Schwann cell

All axons of the peripheral nerves are ensheathed by rows of Schwann
cells.
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Introduction to the Schwann cell
The Schwann cell

Nerve cells and Schwann cells are dependent on each other for normal development,
function and maintenance.

For example, it is the axon that controls the initiation of myelination, the number of
myelin lamellae and the maintenance of the complex Schwann cell organisation.

However, it is the Schwann cell that regulates axonal diameter, neurofilament spacing
and phosphorylation, and the clustering of ion channels at the node of Ranvier in
myelinated axons.

Furthermore, Schwann cells have the capacity to interact with cells from outside the
nervous systems, as evidenced by their well established ability to communicate with
cells of the immune system.
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Introduction to the Schwann cell
Types of Schwann cells

Schwann cells in the mature PNS can be categorised for convenience by
their morphology, antigenic phenotype, biochemistry and anatomical
location. These categories are:
1: Myelinating Schwann cells (MSCs)
2: Non-myelinating Schwann cells (NMSCs)
3: Perisynaptic Schwann cells (PSCs)
4: Satellite cells
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Satellite cells
Nonmyelinating Schwann cells
Perisynaptic Schwann cells
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Myelinating Schwann cells
Schwann cell development and myelination
Introduction

The glial cells of adult peripheral nerves, myelinating and non-myelinating
Schwann cells, are generated during development from neural crest cells.

The protracted embryonic period of gliogenesis involves first the generation of
Schwann cell precursors and subsequently the generation of immature Schwann
cells.

In the postnatal myelinating or non-myelinating Schwann cells are generated
from immature Schwann cells.
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Schwann cell development and myelination
Schwann cell development
The generation of Schwann cells from neural crest cells is defined by three
major transitions:
1: From neural crest cells to Schwann cell precursors
2: From Schwann cell precursors to immature Schwann cells
3: The divergence of this population into the two mature Schwann cell types
(myelinating and non-myelinating)
Most of these events hinge on axonal signals including survival signals,
mitogenic signals and differentiation signals.
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Schwann cell development and myelination
Schwann cell development
E 14/15 in rat
E12/13 in mouse
E17/18 in rat
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Schwann cell development and myelination
Schwann cell development
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Schwann cell development and myelination
Myelination

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
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Myelination occurs over an extended period during the first three weeks of postnatal life
in rodents, and in humans during a period that begins in embryonic life and ends with
puberty.
Considerable evidence now exists for the idea that positive and negative signals are
involved.
Just before the onset of myelination at E18, significant changes occur in the relationship
between Schwann cells and axons.
They involve radial sorting, a radical change in cellular relationships that allows
Schwann cells to start myelinating single large diameter axons.
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Schwann cell development and myelination
Myelination

At the same time Schwann cell numbers are adjusted by controlling survival and
proliferation and premature myelination appears to be prevented by the activity of
signalling systems that function as ‘myelination brakes’.
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Schwann cell development and myelination
Myelination
The myelin lamellae can be divided
into two domains:
1: compact myelin
2: non-compact myelin
Compact myelin is highly enriched in
lipids, including the glycolipids
galactocerebroside and sulphatide.
P0 (the most abundant protein),
PMP22 and MBP are proteins of the
PNS myelin.
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Cytokine and chemokine interactions with Schwann cells
Introduction

Cytokines, first described as products of the cells of the inflammatory/immune
system.

Neuroglial cells, in particular astrocytes, Schwann cells and microglia respond
to cytokines by changes in function and phenotype and can themselves
produce many of the classically described inflammatory cell cytokines.

Recent studies showing that such cytokines, particularly when produced by
cells that are endogenous to the PNS and CNS, are important in PNS and CNS
development and perhaps in protection and regeneration of the PNS and CNS
in inflammatory, traumatic and even some degenerative diseases.
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Cytokine and chemokine interactions with Schwann cells
Introduction
Schwann cell-cytokine interactions can be studied in various ways:
1: Examining tissue obtained at different stages of development.
2: At different phases of experimental and naturally occurring diseases.
3: Employing different in vitro models.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
1: MHC expression:
IFN-γ induces upregulation of expression of both MHC I and MHC II molecules
on the surface of Schwann cells.
2: Expression of adhesion molecules:
 Unfractionated cytokines, obtained from mitogen stimulated rat spleen cells
(inflammatory cells), as well as IFN-γ, TNF-α and IL-1β upregulated expression of
ICAM-1 (CD54).
Incubation of Schwann cells with other cytokines including IL-1β, IL-2 and TGFβ1, all found in the unfractionated cytokines, had no effect on ICAM-1 expression.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
Expression by TNF-α is predominately via activation of type I TNF-R.
Upregulation of ICAM-1 on Schwann cells can enhance Schwann cell-lymphocyte
interactions.
Interestingly, there was no effect of IFN- γ, TNF- α or IL-1β on expression of two
integrins, LFA-1α (CD11a) and LFA-1β.
Thus the effect on ICAM-1 expression is not a nonspecific effect on upregulation
of all adhesion molecules.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
3: Effect on Schwann cell proliferation:
It has been shown that unfractionated cytokines stimulate Schwann cell proliferation.
TGF-β1 act as a Schwann cell mitogen.
In one study it has been shown that IL-1α and IL-6 are co-mitogens for Schwann
cells, and demonstrated the presence of functional receptor for IL-1 on Schwann cells.
TGF-β, has been shown by several groups to induce Schwann cell proliferation at
suboptimal concentrations and can act as a co-mitogen with IL-1.
These findings are relevant to Schwann cell responses to cytokines in vivo, since
proliferation is important during development of the PNS as well as during recovery
and repair in response to disease.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
4: Effect on Schwann cell viability:
Studies of TNF-α failed to demonstrate a cytotoxic effect on Schwann cells in
myelinating cultures although it has been demonstrated that both the p55 and p75 receptors
for TNF are present on rat Schwann cells.
Somewhat unexpectedly, it has been observed that while TGF-β1 alone induced a
modest amount of Schwann cell death, when added to TNF-α there was a marked
cytotoxic effect.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
5: Effect on Schwann cell development and maturation:
Upregulation of galactolipids and MAGs are considered indicators of Schwann cell
differentiation towards the myelinating phenotype, whereas expression of NGFRp75 is
characteristic of promyelinating or non-myelinating phenotype.
High concentrations of intracellular cAMP can induce myelination. Interestingly, low
concentrations of cAMP induce Schwann cell proliferation.
It has been shown that supernatants obtained from activated inflammatory cells inhibit
cAMP-induced upregulation of surface expression of galactoplipids and also reversed
ongoing maturation of Schwann cells. These supernatants induced Schwann cell
proliferation.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
The Schwann cells incubated with IFN-γ, TNF-α, TGF-β1 , IL-1α, IL-1β, IL-2 and IL-6
separately.
It has been shown that IFN-γ, TNF-α and TGF-β1 inhibited cAMP-induced Schwann
cell maturation as assessed by upregulation of galactoplipid expression and
downregulation of NGFRp75 expression.
TGF-β has been shown to inhibit myelin wrapping of axons by Schwann cells in coculture experiments.
These findings suggest that increased levels of TGF-β within areas of demyelination
may inhibit remyelination.
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Cytokine and chemokine interactions with Schwann cells
In vitro studies of cytokine and Schwann cell interactions
6: Schwann cell synthesis of cytokines:
It has been shown that Schwann cells are able to upregulate genes for several cytokines
as well as produce proteins in vitro.
For most of the cytokines this expression of cytokines and specific mRNAs can be
shown in vivo.
It has been demonstrated that stimulated Schwann cells upregulate mRNA for IL-1α and
β, IL-1RA and IL-1R type I and also synthesis functionally active IL-1.
IL-1, IL-1R and IL-1RA are also expressed in Schwann cells in vivo as well.
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Cytokine and chemokine interactions with Schwann cells
Cytokines and Schwann cells in diseases of the PNS
It is important to consider that cytokines are prominent mediators of inflammatory/
immune demyelinating disorders of the PNS.
Many studies support a critical role for cytokines in the pathogenesis of PNS diseases
as well as in recovery from many of these disorders.
Acute inflammatory demyelinating polyneuropathy (AIDP)
Diabetic neuropathy
Neurofibromatosis type 1 (NF1)
Leprosy
For example increased levels of several cytokines, including TNFα, have been
reported in serum of patients with GBS.
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Cytokine and chemokine interactions with Schwann cells
Cytokines and Schwann cells in diseases of the PNS
In NF1, Schwann cells heterozygous for the NF1 mutation (NF1-/-) secrete five
times the normal amount of kit ligand (stem cell factor), which in turn serves as a
chemoattractant for mast cells.
Whether the cytokines and growth factors secreted by the activated mast cells act
to maintain the Schwann-cellderived neurofibromas in a benign state, or influence
progression to malignant nerve sheath tumours is not known.
In leprosy, cytokines are also postulated to influence disease progression.
In experimental autoimmune neuritis (EAN), PNS animal models, genes and gene
products for several cytokines, including interleukin-1 (IL-1), IL-6, TNF-α and TGFβ are upregulated in the PNS.
It has been shown that intraneural injection of TNF-α or IL-12, a proinflammatory
cytokine produced predominately by cells of the monocyte/macrophage lineage,
induces inflammation and demyelination.
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Cytokine and chemokine interactions with Schwann cells
Cytokines, Schwann cells and PNS regeneration
 Trauma to the PNS often results in damage or transection of axons, leading to loss of
myelination.
 Inflammatory cells, primarily macrophages, infiltrate the nerve and phagocytose
cellular debris including myelin.
 It has been shown that macrophage infiltration is important in regeneration.
 Administration of IL-1 receptor antagonist (IL-1RA) also inhibits regeneration,
suggesting that IL-1 is an important factor in PNS response to trauma.
 It has been shown that IL-1 induces NGF production by Schwann cells and fibroblasts.
 It is likely that the production of NGF is important in regeneration.
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Cytokine and chemokine interactions with Schwann cells
Chemokines and Schwann cells in diseases of the PNS

There have been several studies demonstrating several chemokines of both the
CXC (alpha chemokines) and CC (beta chemokines) chemokines in the PNS and
specifically in Schwann cells.
 MCP-1 (CCL2), MIP-1α (CCL3) and RANTES (CCL5) are upregulated in the
PNS after peripheral nerve transection.
 In one study it was shown that the earliest increase of MCP-1 was seen in
Schwann cells, peaking in those cells at 24 h, and observed in inflammatory cells
and endothelial cells later in the evolution of the lesion.
 MIP-1α-positive cells were seen by 24 h after trauma, but the expression in
Schwann cells was seen at 5 days.
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Cytokine and chemokine interactions with Schwann cells
Chemokines and Schwann cells in diseases of the PNS
 MIP-1a was also upregulated in Schwann cells present in PNS tumours,
suggesting that the chemokine contributes to the recruitment of macrophages into
Schwann-cell-derived tumours.
 In Guillain-Barre syndrome (GBS) there was upregulation of MCP-1 in Schwann
cells as well as inflammatory cells.
 CCR2, the receptor for MCP-1, was seen, but at low levels.
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Cytokine and chemokine interactions with Schwann cells
Chemokines and Schwann cells in diseases of the PNS
 SDF-1β predominates in embryonic and early postnatal stages of development,
and SDF-1γ is more highly expressed in adult PNS.
 Neurons and Schwann cells are the predominant SDF-1 expressing cells.
 After trauma SDF-1β is transiently increased, suggesting that SDF-1β is important
in PNS development and in repair from trauma.
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Cytokine and chemokine interactions with Schwann cells
Conclusion

Cytokine and chemokine interactions with Schwann cells, as well as expression
and production of cytokines and chemokines by Schwann cells, are important in
the pathogenesis of several different types of disease of the PNS in normal
development and PNS repair.

Additional in vitro and in vivo studies are clearly needed to further elucidate the
role of these cytokines and chemokines in health and disease.
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Schwann cells as immunomodulatory cells
Introduction

The nervous system is an immunologically privileged site.
?
 The blood-nerve barrier (BNB) does restrict access of immune cells and soluble
mediators to a certain degree; however, this restriction is not complete, either
anatomically (e.g. the BNB is absent or relatively deficient at the roots, in the
ganglia and the motor terminals) or functionally.
 Activated T lymphocytes can penetrate intact barriers irrespective of their antigen
specificity, and, under certain circumstances, release cytokines that upregulate the
expression of major histocompatibility complex MHC II molecules, key molecules
required for antigen presentation.
 In the central nervous system (CNS) tissue-resident neuroglial cells are present that
actively participate in the regulation of immune responses within the tissue.
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Schwann cells as immunomodulatory cells
Schwann cells as immunomodulatory cells
 In recent years, several lines of evidence have pointed to Schwann cells as
immunocompetent cells within the peripheral nervous system (PNS), which, in
addition to their physiological roles, exhibit a broad spectrum of immune-related
functions and might be involved in the local immune response in the PNS.

Spectrum of an immune response can be displayed by Schwann cells; recognition
of antigens, presentation of antigens, mounting an immune response, and, finally,
terminating an immune response within the inflamed peripheral nerve.
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Schwann cells as immunomodulatory cells
Antigen recognition by Schwann cells
 The family of toll-like receptors (TLRs) belong to the group of pattern-recognition
receptors that are key to recognising specific conserved components of microbes
such as LPS.
 TLRs are usually found on antigen presenting cells, such as dendritic cells.
 TLR-2 has been shown to be constitutively expressed on primary human and rat
Schwann cells, and has been invoked as a target receptor for M. leprae.
 Under inflammatory conditions, expression of various TLRs, especially TLR-4, is
inducible on rat Schwann cells in vitro.
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Schwann cells as immunomodulatory cells
Schwann cells as antigen-presenting cells
 It has been shown that human and rat Schwann cells in vitro constitutively express
low levels of MHC class I but not MHC class II.
 In human nerve biopsies from patients with GBS and its chronic variant, CIDP
Schwann cells stained positive for MHC class II.
 This suggests that these cells may indeed act as APC in immune-mediated disorders
of the PNS.

Schwann cells in vitro have been shown to present foreign and exogenous
autoantigen, such as MBP, to antigen-specific syngeneic T line cells.
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Schwann cells as immunomodulatory cells
Schwann cells as antigen-presenting cells
 Recent data suggest that BB-1, a member of the family of co-stimulatory
molecules, can be detected on unmyelinated Schwann cells and appears
upregulated on myelinating Schwann cells in nerve biopsies from CIDP patients.

These findings suggest that Schwann cells possess the necessary markers enabling
them to act as an APC in the inflamed PNS.
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Schwann cells as immunomodulatory cells
Schwann cells as regulators of immune response
 For a long time cytokines as mediators of an immune response within the
peripheral nerve were considered to be the exclusive product of inflammatory
cells.
 There is now a large body of evidence implying that Schwann cells are capable of
producing and secreting a large variety of cytokines, which could act as
immunomodulators.
 IL-1 (initiator of immune response), in addition, other proinflammatory cytokines,
such as IL-6, TNF-α, and TGF-β are generated and released by Schwann cells
under certain conditions, some in vitro, others also in vivo.
 Other proinflammatory and immunoregulatory mediators, such as PGE2, Tx A2
and LTC4, are synthesised in large amounts by Schwann cells, and may regulate
the immune cascade within the inflamed PNS.
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Schwann cells as immunomodulatory cells
Schwann cells as regulators of immune response
 NFkB plays a pivotal role in the regulation of the host innate antimicrobial
response.
 It governs the expression of many immunological mediators, including
cytokines, their receptors and components of their signal transduction.
 Recent studies suggest that two NF-kB complexes, p65/p50 and p50/p50, can
be activated and regulated in human Schwann cells under certain conditions.
 Interestingly, the natural inhibitor of NF-kB, IkB, can also be detected in large
amounts in Schwann cells.
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Schwann cells as immunomodulatory cells
Schwann cells as terminators of the immune response
 In order to control the massive expansion of cellular and soluble immune
mediators within the target tissue, certain mechanisms must operate with high
fidelity to regulate the immune response.
 Schwann cells reveal surface expression of FasL after stimulation with
proinflammatory cytokines in vitro.
 Functional analysis indicates that the interaction between Fas on T cells and
FasL on Schwann cells promotes apoptosis of T lymphocytes.
 This raises the possibility that Schwann cells are important in terminating the
immune response in the inflamed PNS.
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Schwann cells as immunomodulatory cells
Summary
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Guillain-Barre syndrome and the Schwann cell
Introduction

Guillain-Barre´ syndrome (GBS) was introduced by Guillain, Barre´ and
Strohl in 1916.

GBS is an immunologically PNS disease that characterized by progressive
weakness of the limbs reaching its worst typically within four weeks and loss
of the tendon reflexes.

About two thirds of patients with GBS develop symptoms of peripheral
neuropathy between one and six weeks after symptoms of an antecedent
infection, most commonly an upper respiratory infection but also after
gastrointestinal infection.

Campylobacter jejuni, EBV and Mycoplasma pneumoniae
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Guillain-Barre syndrome and the Schwann cell
Types of GBS

GBS consists of three subtypes:
1: Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (in Europe and
North America)
2: Acute motor axonal neuropathy (AMAN) (in china and east Asia)
3: Acute motor and sensory axonal neuropathy (AMSAN)
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Guillain-Barre syndrome and the Schwann cell
GBS and the Schwann cell
GBS is characterized by the
infiltration of macrophages and T cells
into the endoneurium and myelin sheath.
In moderate disease, axons are not
attacked and hence they remyelinate
after few weeks.
Schwann cells synthesize neurotropic
factors, growth factors, neurite
promoting factors and cell adhesion
molecules that help in regenerating the
peripheral nerve axons.
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Schwann cells: The present and the future
Introduction

Cell transplant therapies are currently under active consideration for a number of
degenerative diseases.

In the immune-mediated demyelinating-neurodegenerative disease multiple sclerosis
(MS), only the myelin sheaths of the CNS are lost, while Schwann cell myelin of the
PNS remains normal.
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Schwann cells play a crucial role in endogenous repair of peripheral nerves due to their
ability to dedifferentiate, migrate, proliferate, express growth promoting factors, and
myelinate regenerating axons.
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On the other hand following spinal cord injury (SCI), Schwann cells migrate from
periphery into the injury site, where they apparently participate in endogenous repair
processes.

These, and the finding that Schwann cells can myelinate CNS axons, has focused
interest on Schwann cell transplants to repair myelin in MS and SCI.
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Schwann cells: The present and the future
Schwann cells transplant for CNS repair
Therapeutic strategies for MS:
1: Attempts to block the disease process
2: Attempts to repair the damage, notably the demyelination, caused by the disease

Stimulation of the inherent remyelination capacity of the CNS

Myelin repair
Transplantation of exogenous cells that can populate the MS
lesions, remyelinate the axons and prevent further axon loss.
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Schwann cells: The present and the future
Schwann cells transplant for CNS repair

Choice of cell type for transplantation:
1: Cells from various stages of the oligodendrocyte lineage
2: Olfactory bulb ensheathing cells
3: Schwann cells from the post-natal PNS
 It has been shown that transplanted Schwann cells myelinate CNS axons in vivo in a
variety of experimental models, and can restore function to demyelinated axons.
 In one study it has been shown that transplantation of Schwann cells to subarachnoid
space induces repair in contused rat spinal cord (Masoumeh Firouzi et al. 2008).
 Indeed Schwann cells were chosen for the first clinical trial of transplanted cells in
MS patients.
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Schwann cells: The present and the future
Potential drawbacks to the use of Schwann cells

Potential drawbacks to the use of Schwann cells within the CNS:
1: Migration
 Unfortunately according to most studies, implanted Schwann cells do not migrate significantly
through the normal CNS.
2: Survival
 Schwann cells appear to survive very poorly in normal CNS, although in lesions where the cells
can access naked axons and myelinate, they thrive.
3: Complex interplay between astrocytes and Schwann cells
 Studies show that co-existence or close interaction between astrocytes and Schwann cells, in vivo
or in vitro, is rarely obtained, and that under most conditions astrocytes inhibit Schwann cell
myelination in the CNS.
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Schwann cells: The present and the future
Potential drawbacks to the use of Schwann cells
4: Ethical and immunological compatibility issues
 Use of fetal tissue as a source for Schwann cells and MHC incompatibility
5: Preparation of enough cells for effective transplantation
 It is necessary to generate enough cells as soon as possible because of progressive nature
of spinal injuries and limited time window for effective therapy
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Schwann cells: The present and the future
Strategies for the future
1: Use of Schwann cell precursors (SCPs) instead of mature Schwann cells
 It has been shown that implanted SCPs from embryo day 14 (E14) rat nerves into CNS survive well,
migrate through normal CNS tissue, interface smoothly and intimately with host glial cells and
myelinate.
2: The use of host-derived, autologous peripheral nerves as a source for Schwann cells
3: Improve methods to generate enough cells for transplantation
4: Combinatorial therapy
 It has been shown that co-transplantation of olfactory ensheathing glia (OEG) with Schwann cells
promotes efficacy of therapy in SCI.
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Thank you for attention
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